Fatigue and exercise intolerance are major symptoms of congestive heart failure (CHF), yet indices of cardiac function correlate poorly with exercise capacity, suggesting an important contribution of peripheral abnormalities. Our recent work indicates that the primary physiologic change in muscle is increased fatiguability and that the resulting decreased muscle endurance correlates closely with impairment of exercise tolerance. The aims of the present proposal are: (1) to determine whether the mechanism of muscle fatigue is impaired central drive or altered muscle function; (2) to determine whether CHF patients exhibit the same close relationship between Pi and force as normal subjects, which would suggest that the mechanism of fatigue is metabolic; (3) to determine the role of skeletal muscle blood flow, activity of oxidative and glycolytic enzymes, and muscle atrophy in producing the metabolic changes in muscle; and (4) to define the role of deconditioning in the abnormalities of skeletal muscle in CHF. Studies will be conducted both in human subjects and the rat infarction model of CHF. To address Aim 1 peroneal nerve stimulation will be employed during progressive tibialis anterior exercise to determine whether maximal voluntary force can be potentiated, which would suggest an abnormality of central drive. To address Aim 2, the relationships between muscle metabolism and force in CHF patients and animals will be examined utilizing (31P-MRS) and compared to those of appropriate controls. Aim 3 will be approached by measuring muscle size (by MRI in patients, by weight in animals), blood flow (by venous occlusion plethysmography in patients, with radioactive microspheres in rats), and the activity of oxidative and glycolytic enzymes and by determining the relationship of the observed metabolic changes to these measurements. Several studies will be performed to address Aim 4. The first will be to quantify fatigue and the force-metabolism relationships in a muscle which is unlikely to be deconditioned in mild to moderate CHF (the masseter) and one which would be affected by inactivity (the tibialis anterior). Concordant abnormalities would suggest a primary change in muscle, whereas the finding of abnormalities in the tibialis alone would suggest a role for deconditioning. We will also examine the effect of deconditioning normal subjects on muscle force, metabolism, blood flow, size and biochemistry to determine whether changes similar to those observed in CHF evolve. Finally, in the rat model we will determine whether low level exercise training will prevent the evolution of the metabolic changes in CHF. Taken together, the results of these studies should determine the mechanism and physiologic importance of abnormalities of muscle function and metabolism in CHF.